This invention relates to heterocyclic compounds, and more specifically to such compounds that bind with high selectivity and high affinity to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of certain central nervous system (CNS) diseases.
The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, xcex3-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization.
A number of cDNAs for GABAA receptor subunits have been characterized. To date at least 6xcex1, 3xcex2, 3xcex3, 1xcex5, 1xcex4 and 2xcfx81 subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2xcex1, 2xcex2, and 1xcex3 subunits (Pritchett and Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are xcex11xcex22xcex32, xcex12xcex23xcex32, xcex13xcex23xcex32, and xcex15xcex23xcex32(Mohler et. al. Neuroch. Res. 1995; 20(5): 631-636).
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site, the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines is enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABAA receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABAA receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABAA selective ligands may also act to potentiate the effects of certain other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABAA selective ligands than when used alone.
This invention provides heterocyclic compounds, such as 5,6-Dihydro-4H-1,3a,6-triaza-as-indacenes and related compounds, that bind with high affinity and high selectivity to the benzodiazepine site of the GABAA receptor, including human GABAA receptors.
Thus, the invention provides novel compounds of Formula A (shown below), and pharmaceutical compositions comprising compounds of Formula A.
The invention further comprises methods of treating patients suffering from certain CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from certain CNS disorders with an effective amount of a compound of the invention is encompassed by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering an effective amount of a compound of the invention with another CNS active compound.
Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABAA receptors in tissue sections.
Accordingly, a broad aspect of the invention is directed to compounds of Formula A: 
or a pharmaceutically acceptable salt thereof, wherein:
the b-ring is a 5-9 membered ring;
E represents (CR1R2)k, xe2x80x94CR1xe2x95x90CR2xe2x80x94, xe2x80x94Oxe2x80x94(CR1R2)kxe2x80x94, xe2x80x94(CR1R2)kxe2x80x94Oxe2x80x94, xe2x80x94Nxe2x95x90CR1xe2x80x94, xe2x80x94CR1xe2x95x90Nxe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94(CR1R2)kxe2x80x94, or xe2x80x94(CR1R2)kxe2x80x94NRxe2x80x2xe2x80x94, wherein
R1 and R2 independently represent
hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or
phenyl, pyridyl, phenyl(C1-C6)alkyl, or pyridyl(C1-C6)alkyl, where each phenyl or pyridyl is optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C1-C6)alkylamino;
k is 0, 1, 2, or 3;
Rxe2x80x2 represents
hydrogen, C1-C6 alkyl, C2-C7 alkanoyl, C1-C6 alkoxy(C1-C6)alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C3-C6)alkyl, or
aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, where each aryl and heteroaryl is optionally substituted with up to 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- and di(C1-C6)alkylamino;
G is oxygen or NH;
J represents (CR5R6)d where
d is 0 or 1; and
R5 and R6 together form a carbonyl group; or
R5 and R6 are independently hydrogen or R100,
where each R100 is independently selected from halogen, hydroxy, nitro, cyano, R10, amino, xe2x80x94NH(R10), xe2x80x94N(R10)(R10), xe2x80x94COOH, xe2x80x94O(R10), xe2x80x94SO2NH2, xe2x80x94SO2NH(R10), xe2x80x94SO2N(R10)(R10) xe2x80x94NHCO(R10), xe2x80x94N(R10)CO(R10), xe2x80x94NHCO2(R10), xe2x80x94N(R10)CO2(R10), xe2x80x94NHSO2(R10), xe2x80x94N(R10)SO2(R10), xe2x80x94SO2NHCO(R10), xe2x80x94SO2N(R10)CO(R10) xe2x80x94CONHSO2(R10), xe2x80x94CON(R10)SO2(R10), xe2x80x94CONH2, xe2x80x94CONH(R10), xe2x80x94CON(R10)(R10), xe2x80x94CO2(R10), xe2x80x94CO(R10), xe2x80x94SR10, SO(R10), xe2x80x94SO2 (R10), aryl having from 1 to 3 rings, and heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ring, and in at least one of said rings from 1 to about 3 heteroatoms selected from nitrogen, oxygen and sulfur, and where each aryl and heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C1-C6)alkylamino;
each R10 is independently a straight, branched, or cyclic alkyl group having up to 8 carbon atoms, contains zero or one or more double or triple bonds, and is optionally substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, mono- or di-(C1-C6)alkylamino, cyano, nitro, C1-C6alkoxy, xe2x80x94COOH, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-C6alkyl), xe2x80x94SO2N(C1-C6alkyl)(C1-C6alkyl), xe2x80x94NHCO(C1-C6alkyl) xe2x80x94N(C1-C6alkyl)CO(C1-C6alkyl), NHCO2(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)CO2(C1-C6alkyl), xe2x80x94NHSO2(C1-C6alkyl), xe2x80x94N(C1-C6alkyl)SO2(C1-C6alkyl), xe2x80x94SO2N(C1-C6alkyl)CO(C1-C6alkyl), xe2x80x94SO2NHCO(C1-C6alkyl), xe2x80x94CON(C1-C6alkyl)SO2(C1-C6alkyl), xe2x80x94CONHSO2(C1-C6alkyl), xe2x80x94CONH2, xe2x80x94CONH(alkyl), xe2x80x94CON(alkyl)(alkyl), xe2x80x94CO2(alkyl), xe2x80x94CO(alkyl), xe2x80x94SO0-2(C1-C6alkyl), and C3-C7cycloalkyl;
the group 
xe2x80x83is the A ring and represents an optionally substituted saturated, partially unsaturated, or aromatic heterocyclic ring containing at least one nitrogen, oxygen, or sulfur atom,
where the A ring is optionally substituted with up to three groups independently selected from R100;
V is nitrogen, carbon, or CH;
Y is carbon or CH;
X is hydrogen, hydroxy, amino, mono- or di(C1-C6)alkylamino, C1-C6 alkyl, or C1-C6 alkoxy;
T is hydrogen, halogen, hydroxy, amino, mono- or di(C1-C6) alkylamino, C1-C6 alkyl, or C1-C6 alkoxy;
Q is a saturated carbocyclic or heterocyclic group, partially unsaturated carbocyclic or heterocyclic group, an aryl group, or heteroaryl group, where each group has from 1 to 3 rings where each ring contains from 3 to 8 ring members, and where each heterocyclic and heteroaryl group contains at least one ring having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; and
where each carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally substituted with 1, 2, or 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, oxo, cyano, nitro, amino, C1-C6 haloalkyl, C1-C6 haloalkoxy, and mono- or di(C1-C6)alkylamino;
W is a bond, oxygen, NH, sulfur, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1C2xe2x80x94, or CR7R8 where R7 and R8 are the same or different and represent hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, or C1-C6 alkoxy(C1-C6)alkyl, or CR7R8 represents C3-C7 cycloalkyl;
Z is hydrogen, hydroxy, hydroxy(C1-C6)alkyl, C1-C6 alkoxy, xe2x80x94CO(C1-C6)alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C6)alkyl, C3-C7 cycloalkyl(C1-C4)alkoxy, amino, mono- or di(C1-C6)alkylamino, or NR11COR12 where R11 and R12 are the same or different and represent hydrogen or C1-C6 alkyl, or NCOR11R12 represents a heterocycloalkanone ring, or
Z is a saturated carbocyclic or heterocyclic group, a partially unsaturated carbocyclic or heterocyclic group, an aryl group, or a heteroaryl group, where each group has from 1 to 3 rings where each saturated ring contains from 3 to 8 ring members and each aromatic or partially unsaturated ring contains from 5-8 ring members, and where each heterocyclic and heteroaryl group contains at least one ring having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur; and
where each carbocyclic, heterocyclic, aryl, and heteroaryl group is optionally substituted with 1, 2, or 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, C1-C6 haloalkyl, C1-C6 haloalkoxy, and mono- or di(C1-C6)alkylamino; 
xe2x80x83independently represent saturated carbon chains optionally substituted with one or more substituents independently selected from halogen, cyano, nitro, amino, mono- or di(C1-C6)alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl, and C3-C7 cycloalkyl;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
The invention also provides intermediates and methods useful for preparing the compounds of Formula A.
Preferred compounds of Formula A include those where G is a nitrogen atom carrying C1-C6 alkyl or, preferably, hydrogen.
Other preferred compounds of Formula A are those where the group 
(hereinafter xe2x80x9cArxe2x80x9d) represents
phenyl, pyridyl, pyrimidinyl, triazolyl, thiazolyl, thiadiazolyl, quinolinyl, pyrazolyl, isoxazolyl, pyrazinyl, triazolyl(C1-C6)alkyl, pyridazinyl, 2-oxo-3-hydropyridyl, oxazole, oxadiazolyl, benzimidazol-5-yl, each of which is optionally substituted with 1, 2 or 3 groups independently selected from
halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C3)alkyl, C1-C6 alkylthio, C1-C6 alkylamino, C3-C7 cycloalkylamino, C3-C7 cycloalkyl(C1-C3)alkylamino, C1-C6 alkoxycarbonylamino(C1-C6)alkyl), C1-C6 alkoxycarbonyl((C1-C6)alkyl)amino(C1-C6)alkyl), C1-C6 alkylamino(C1-C6)alkoxy, furanyl, (4-benzylpiperidinyl)(C1-C6)alkoxy, (4-benzylpiperazinyl)(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkylamino, morpholinyl(C1-C6)alkoxy, trifluoromethyl, C1-C6 haloalkoxy, 1,3-dioxolanyl, ethyl-methanesulfonylamino(C1-C6)alkoxy, 1,4-dioxepinyl, 1,4-dioxanyl, phenyoxy, pyrrolidinyl(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, C1-C4 alkylamino(C1-C4)alkyl, imidazolyl, imidazolyl(C1-C6)alkyl, imidazolyl(C1-C6)alkoxy, triazolyl(C1-C6)alkyl, benzyloxy(C1-C6)alkoxy, piperidinyl(C1-C6)alkyl, piperazinyl(C1-C6)alkyl, morpholinyl(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl, azetidinyl(C1-C6)alkoxy, azetidinyl(C1-C6)alkyl, C1-C4 alkoxy(C1-C4)alkylamino(C1-C4)alkyl, C1-C6 alkanoyl(C1-C6)alkoxy, C1-C6 alkoxyphenoxy, phenoxy substituted with halo(C1-C6)alkyl, tetrahydrofuranyloxy, oxetanyl(C1-C6)alkoxy, oxetanyl(C1-C6)alkyl, and 1-benzylimidazolyl(C1-C6)alkoxy.
More preferred Ar groups include
phenyl, pyridyl, pyrimidinyl, 2-oxo-3-hydropyridyl, isoxazolyl, and oxazolyl, each of which is optionally substituted with 1 or 2 groups independently selected from
halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C3)alkyl, C1-C6 alkylthio, C1-C6 alkylamino, C3-C7 cycloalkylamino, C3-C7 cycloalkyl(C1-C3)alkylamino, C1-C6 alkoxycarbonylamino(C1-C6)alkyl), C1-C6 alkoxycarbonyl((C1-C6)alkyl)amino(C1-C6)alkyl), C1-C6 alkylamino(C1-C6)alkoxy, furanyl, (4-benzylpiperidinyl)(C1-C6)alkoxy, (4-benzylpiperazinyl)(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkylamino, morpholinyl(C1-C6)alkoxy, trifluoromethyl, C1-C6 haloalkoxy, 1,3-dioxolanyl, ethyl-methanesulfonylamino(C1-C6)alkoxy, 1,4-dioxepinyl, 1,4-dioxanyl, phenyoxy, pyrrolidinyl(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, C1-C4 alkylamino(C1-C4)alkyl, imidazolyl, imidazolyl(C1-C6)alkyl, imidazolyl(C1-C6)alkoxy, triazolyl(C1-C6)alkyl, benzyloxy(C1-C6)alkoxy, piperidinyl(C1-C6)alkyl, piperazinyl(C1-C6)alkyl, morpholinyl(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl, azetidinyl(C1-C6)alkoxy, azetidinyl(C1-C6)alkyl, C1-C4 alkoxy(C1-C4)alkylamino(C1-C4)alkyl, C1-C6 alkanoyl(C1-C6)alkoxy, C1-C6 alkoxyphenoxy, phenoxy substituted with halo(C1-C6)alkyl, tetrahydrofuranyloxy, oxetanyl(C1-C6)alkoxy, oxetanyl(C1-C6)alkyl, and 1-benzylimidazolyl(C1-C6)alkoxy.
Particularly preferred Ar groups include
phenyl, pyridyl, pyrimidinyl, and 2-oxo-3-hydropyridyl, each of which is optionally substituted with 1 or 2 groups independently selected from
halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C3)alkyl, C1-C6 alkylthio, C1-C6 alkylamino, C3-C7 cycloalkylamino, C3-C7 cycloalkyl(C1-C3)alkylamino, C1-C6 alkoxycarbonylamino(C1-C6)alkyl), C1-C6 alkoxycarbonyl((C1-C6)alkyl)amino(C1-C6)alkyl), C1-C6 alkylamino(C1-C6)alkoxy, furanyl, (4-benzylpiperidinyl)(C1-C6)alkoxy, (4-benzylpiperazinyl)(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkylamino, morpholinyl(C1-C6)alkoxy, trifluoromethyl, C1-C6 haloalkoxy, 1,3-dioxolanyl, ethyl-methanesulfonylamino(C1-C6)alkoxy, 1,4-dioxepinyl, 1,4-dioxanyl, phenyoxy, pyrrolidinyl(C1-C6)alkoxy, hydroxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, C1-C4 alkylamino(C1-C4)alkyl, imidazolyl, imidazolyl(C1-C6)alkyl, imidazolyl(C1-C6)alkoxy, triazolyl(C1-C6)alkyl, benzyloxy(C1-C6)alkoxy, piperidinyl(C1-C6)alkyl, piperazinyl(C1-C6)alkyl, morpholinyl(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl, azetidinyl(C1-C6)alkoxy, azetidinyl(C1-C6)alkyl, C1-C4 alkoxy(C1-C4)alkylamino(C1-C4)alkyl, C1-C6 alkanoyl(C1-C6)alkoxy, C1-C6 alkoxyphenoxy, phenoxy substituted with halo(C1-C6)alkyl, tetrahydrofuranyloxy, oxetanyl(C1-C6)alkoxy, oxetanyl(C1-C6)alkyl, and 1-benzylimidazolyl(C1-C6)alkoxy.
Highly preferred substituents on the Ar aryl and heteraryl groups include
halogen, C1-C6 alkoxy, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C3)alkyl, C1-C6 alkylamino, C3-C7 cycloalkylamino, C1-C6 alkoxycarbonylamino(C1-C6)alkyl), C1-C6 alkoxycarbonyl((C1-C6)alkyl)amino(C1-C6)alkyl), C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkoxy, C1-C6 alkoxy(C1-C6)alkylamino, morpholinyl(C1-C6)alkoxy, pyrrolidinyl(C1-C6)alkoxy, C1-C4 alkylamino(C1-C4)alkyl, piperidinyl(C1-C6)alkyl, piperazinyl(C1-C6)alkyl, morpholinyl(C1-C6)alkyl, pyrrolidinyl(C1-C6)alkyl, and C1-C4 alkoxy(C1-C4)alkylamino(C1-C4)alkyl.
In addition to compounds of Formula A, the invention also provides compounds of Formula I 
and the pharmaceutically acceptable salts thereof, wherein:
J is defined as above with respect to Formula I;
E is defined as above with respect to Formula I and preferably represents xe2x80x94(CR1R2)kxe2x80x94 where R1 and R2 are independently chosen at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, amino, haloalkyl, mono or diamino(C1-6)alkyl, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl and C1-6 alkoxy, and k is 0, 1, 2, or 3;
the group 
xe2x80x83is a group of the formula: 
xe2x80x83represents a saturated, unsaturated or aromatic heterocyclic ring containing at least one nitrogen, oxygen or sulfur atom, wherein the UY and VY bonds may be single, double or aromatic bonds,
U is nitrogen, NRA, S, or O;
V is nitrogen, carbon or CH;
Y is carbon, or CH;
and said saturated, unsaturated or aromatic heterocyclic ring is chosen from:
thienyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, pyrazinyl, pyridizinyl, piperidinyl, oxazolyl, isoxazolyl, symmetrical and unsymmetrical triazolyl, pyrrolyl, furanyl, diazenyl, triazenyl, 1,2,4-triazolone, 4,5-dihydroimidazolyl, and 1,4,5,6-tetrahydropyrimidinyl,
each of which is optionally substituted at any available nitrogen by RA and optionally substituted at any available carbon by R3 and R4, wherein:
RA is selected from (C1-C6)alkyl, C1-C6 haloalkyl, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkyl, aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, where each aryl and heteroaryl is optionally substituted with up to 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- and di(C1-C6)alkylamino;
R5 and R6 are independently chosen from hydrogen, aryl, heteroaryl, halogen, hydroxy, nitro, cyano, C1-6alkyl1, amino, xe2x80x94COOH, xe2x80x94O(C1-6alkyl1), xe2x80x94NH(C1-6alkyl1), xe2x80x94N(C1-6alkyl1)(C1-6alkyl1), xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-6alkyl1), xe2x80x94SO2N(C1-6alkyl1)(C1-6alkyl1), xe2x80x94N(C1-6alkyl1)CO(C1-6alkyl1), N(C1-6alkyl1)CO2(C1-6alkyl1), xe2x80x94NHSO2(C1-6alkyl1), xe2x80x94N(C1-6alkyl1)SO2(C1-6alkyl1), xe2x80x94SO2NHCO(C1-6alkyl1), xe2x80x94CONHSO2(C1-6alkyl1), xe2x80x94CONH(C1-6alkyl1), xe2x80x94CON(C1-6alkyl1)(C1-6alkyl1), xe2x80x94CO2(C1-6alkyl1), xe2x80x94CO(C1-6alkyl1) and xe2x80x94SO0-2(C1-6alkyl1),
wherein C1-6alkyl1 is independently chosen at each occurrence and is straight branched or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy, carbocylic or heterocyclic group, xe2x80x94COOH, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-4alkyl), xe2x80x94SO2N(C1-4alkyl)(C1-4alkyl), xe2x80x94N(C1-4alkyl)CO(C1-4alkyl), N(C1-4alkyl)CO2(C1-4alkyl), xe2x80x94NHSO2(alkyl), xe2x80x94N(C1-4alkyl)SO2(C1-4alkyl), xe2x80x94SO2NHCO(C1-4alkyl), xe2x80x94CONHSO2(C1-4alkyl), xe2x80x94CONH(C1-4alkyl), xe2x80x94CON(C1-4alkyl)(C1-4alkyl), xe2x80x94CO2(C1-4alkyl), xe2x80x94CO(C1-4alkyl), and -SO02(C1-4alkyl);
R3 and R4 are independently chosen at each occurrence, and are defined the same as R5 and R6;
X is chosen from hydrogen, hydroxy, amino, C1-6 alkyl, and C1-6alkoxy;
T is chosen from hydrogen, halogen, hydroxy, amino, C1-6 alkyl, and C1-6 alkoxy;
Q is a phenyl, naphthyl, quinolinyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, isoxazolyl, symmetrical or unsymmetrical oxadiazolyl, symmetrical or unsymmetrical thiadiazolyl, symmetrical or unsymmetrical triazolyl, pyrazolyl, furanyl, diazenyl, triazenyl, or triazolopyrazinyl group;
each of which may be unsubstituted or substituted with up to three substituents independently selected from i) and ii) wherein
i) represents hydroxy, cyano, halogen, nitro, amino, mono or di(C1-6)alkylamino, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, trifluoromethyl, or trifluoromethoxy;
ii)represents straight or branched chain C1-6alkyl optionally containing heteroatoms and optionally substituted with one or more carbocyclic or heterocyclic group;
W is hydrogen, oxygen, nitrogen, sulfur, or CR7R8 where R7 and R8 are the same or different and represent hydrogen, straight or branched chain C1-6alkyl, or R7 and R8 may be taken together to represent a cyclic moiety having 3-7 carbon atoms;
Z is hydrogen, hydroxy, straight or branched chain C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkyl(C1-3alkoxy), amino, mono or di C1-6alkylamino, a carbocyclic or heterocylic group, or NR9COR10 where R9 and R10 are the same or different and represent hydrogen or straight or branched chain C1-6alkyl, or R9 and R10 may be joined to from a C3-7 cycloalkyl ring, or
Z is a phenyl, napthyl, quinolinyl, thienyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, pyrazinyl, pyridizinyl, piperidinyl, oxazolyl, isoxazolyl, symmetrical or unsymmetrical thiadiazolyl, symmetrical or unsymmetrical triazolyl, symmetrical or unsymmetrical oxadiazolyl, pyrrolyl, furanyl, pyrimidinyl, diazenyl, triazenyl, 1,2,4-triazolone, 4,5-dihydroimidazolyl, or 1,4,5,6-tetrahydropyrimidinyl group; 
xe2x80x83represent a carbon chain optionally substituted with hydrogen, halogen, cyano, nitro, amino, mono or di C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, trifluoromethyl, trifluoromethoxy, straight or branched chain C1-6alkyl, or C3-7cycloalkyl, and
m is 0, 1, 2, or 3; and
n is 0, 1, 2, or 3.
In preferred embodiments of Formula I,
R5 and R6 are independently chosen from hydrogen, aryl where aryl is defined as above with respect to Formula A, heteroaryl where heteroaryl is defined as above with respect to Formula A, halogen, hydroxy, nitro, cyano, C1-6alkyl1, amino, xe2x80x94COOH, xe2x80x94O(C1-6alkyl1), xe2x80x94NH(C1-6alkyl1), xe2x80x94N(C1-6alkyl1)(C1-6alkyl1), xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-6alkyl1), xe2x80x94SO2N(C1-6alkyl1)(C1-6alkyl1), xe2x80x94N(C1-6alkyl1)CO(C1-6alkyl1), N(C1-6alkyl1)CO2(C1-6alkyl1), xe2x80x94NHSO2(C1-6alkyl1), xe2x80x94N(C1-6alkyl1) SO2(C1-6alkyl1), xe2x80x94SO2NHCO(C1-6alkyl1), xe2x80x94CONHSO2(C1-6alkyl1), xe2x80x94CONH(C1-6alkyl1), xe2x80x94CON(C1-6alkyl1)(C1-6alkyl1), xe2x80x94CO2(C1-6alkyl1), xe2x80x94CO(C1-6alkyl1) and xe2x80x94SO0-2(C1-6alkyl1),
wherein C1-6alkyl1 is independently chosen at each occurrence and is straight branched or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy, carbocylic or heterocyclic group, xe2x80x94COOH, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-4alkyl), xe2x80x94SO2N(C1-4alkyl)(C1-4alkyl), xe2x80x94N(C1-4alkyl)CO(C1-4alkyl), N(C1-4alkyl)CO2(C1-4alkyl), xe2x80x94NHSO2(alkyl), xe2x80x94N(C1-4alkyl)SO2(C1-4alkyl), xe2x80x94SO2NHCO(C1-4alkyl), xe2x80x94CONHSO2(C1-4alkyl), xe2x80x94CONH(C1-4alkyl), xe2x80x94CON(C1-4alkyl)(C1-4alkyl), xe2x80x94CO2(C1-4alkyl), xe2x80x94CO(C1-4alkyl), and xe2x80x94SO0-2(C1-4alkyl);
R3 and R4 are independently selected at each occurrence, and are defined the same as R5 and R6.
Preferably R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxy, nitro, cyano, C1-6alkyl1, amino, xe2x80x94COOH, xe2x80x94O(C1-6alkyl), xe2x80x94NH(C1-6alkyl), xe2x80x94N(C1-6alkyl)(C1-6alkyl), xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-6alkyl), xe2x80x94SO2N(C1-6alkyl)(C1-6alkyl), xe2x80x94N(C1-6alkyl)CO(C1-6alkyl), N(C1-6alkyl)CO2(C1-6alkyl), xe2x80x94NHSO2(C1-6alkyl), xe2x80x94N(C1-6alkyl) SO2(C1-6alkyl), xe2x80x94SO2NHCO(C1-6alkyl), xe2x80x94CONHSO2(C1-6alkyl), xe2x80x94CONH(C1-6alkyl), xe2x80x94CON(C1-6alkyl)(C1-6alkyl), xe2x80x94CO2(C1-6alkyl), xe2x80x94CO(C1-6alkyl) and xe2x80x94SO02(C1-6alkyl), wherein each C1-6alkyl is independently unsubstituted or substituted with one or more substituents selected from hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy, carbocylic or heterocyclic group, xe2x80x94COOH, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-4alkyl), xe2x80x94SO2N(C1-4alkyl)(C1-4alkyl), xe2x80x94N(C1-4alkyl)CO(C1-4alkyl), N(C1-4alkyl)CO2(C1-4alkyl), xe2x80x94NHSO2(alkyl), xe2x80x94N(C1-4alkyl) SO2(C1-4alkyl), xe2x80x94SO2NHCO(C1-4alkyl), xe2x80x94CONHSO2(C1-4alkyl), xe2x80x94CONH(C1-4alkyl), xe2x80x94CON(C1-4alkyl)(C1-4alkyl), xe2x80x94CO2(C1-4alkyl), xe2x80x94CO(C1-4alkyl), and xe2x80x94SO0-2(C1-4alkyl).
More preferably, R3, R4, R5, and R6 are independently hydrogen, halogen, hydroxy, nitro, cyano, C1-C6 alkyl, amino, C1-C6 alkoxy, mono- or di(C1-C6)alkylamino, hydroxy(C1-C6)alkyl, amino(C1-C6)alkyl or halo(C1-C6)alkyl.
In one embodiment, W is a bond, m is 0, and Z is hydrogen, i.e., 
represents hydrogen. Alternatively, this may be viewed as compounds where W is hydrogen, m is 0, and Z is absent. Thus, in this embodiment, Q is optionally substituted as defined above and also optionally carries an optionally substituted carbon chain as defined above.
More preferred Ar groups include phenyl, 2-pyridyl, 2-pyrazinyl, and 3- or 4-pyrazolyl, each of which is optionally mono- or disubstituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino, or amino(C1-C6)alkyl. Particularly preferred are Ar groups that are unsubstituted or monosubstituted with C1-C4 alkyl, preferably methyl or ethyl. Specific Ar preferred Ar groups include phenyl substituted at the 2-position (ortho to the point of attachment) with C1-C4 alkyl, preferably methyl or ethyl and 4-pyrazolyl substituted in the 1-position with C1-C6 alkyl, preferably methyl, ethyl, or propyl.
Further provided are compounds of Formula II 
and the pharmaceutically acceptable salts thereof,
wherein the variables E, J, R1, R2, R3, R4, R5, R6, k, n, m, T, X, Q, W, and Z are as defined for Formula I.
Compounds of Formula II include compounds where
J is CR5R6;
E is xe2x80x94(CR1CR2)kxe2x80x94 where xe2x80x94R1 and R2 are hydrogen; k is 1 or 2;
R3, R4, R5, and R6, are independently chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and
X and T are both hydrogen (hereinafter compounds of Formula IIa).
Other compounds of Formula II are those where J is CR5R6, E is xe2x80x94CR1CR2xe2x80x94 and R1, R2, R3, R4, R5, and R6 are hydrogen, and k is 1 (compounds of Formula IIb).
Particularly preferred compounds of Formula II are compounds of Formula IIc 
In Formula IIc (above) the conformation of the methyl group at the 4-position of the indacene ring structure denotes (S) stereochemistry.
Other particularly preferred compounds of Formula II are compounds of Formula IId 
In Formula IId, the conformation of the methyl group at the 4-position of the indacene ring structure denotes (R) stereochemistry.
Preferred compounds of Formulas IIc and IId are those where 
represents phenyl optionally substituted with Rp where Rp is C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino, or amino(C1-C6)alkyl.
In another embodiment the invention includes compounds of Formula III 
and the pharmaceutically acceptable salts thereof, wherein the variables E, R1, R2, R3, R4, R5, R6, k, n, m, T, X, Q, W, and Z are as defined for Formula I.
The definition of the variable R3 at the 2-position of the pyridyl ring is independent of it definition at the 3-position.
Specific compounds of Formula III are those where E is xe2x80x94(CR1CR2)kxe2x80x94; k is 2 and R1 and R2 are hydrogen (compounds of Formula IIIa). Other compounds of Formula III are compounds where E is xe2x80x94(CR1CR2)kxe2x80x94; k is 2; R1 and R2 are hydrogen; R3, R4, R5, and R5 are independently chosen at each occurrence from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and T are both hydrogen (compounds of Formula IIIb). Also particularly included as compounds of Formula III are compounds of Formula IIIc and Formula IIId 
wherein each R3 is independently hydrogen or methyl.
Preferred compounds of Formulas IIIc and IIId are those where 
(xe2x80x9cArxe2x80x9d) represents phenyl or pyridyl optionally substituted with Rp where Rp is C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino, or amino(C1-C6)alkyl. Preferably, Ar in IIIc and IIId represents phenyl or 2- or 3-pyridyl each of which is optionally substituted with C1-C6 alkyl, or more preferably unsubstituted or substituted with methyl or ethyl.
The invention also includes compounds of Formula IV 
and the pharmaceutically acceptable salts thereof, wherein the variables E, R1, R2, R3, R4, R5, R6, k, n, m, T, X, Q, W, and Z are as defined for Formula I. Particular compounds of Formula IV are those compounds where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2 and R1 and R2 are hydrogen (compounds of Formula IVa). Other compounds of Formula IV are those compounds were E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2; R1 and R2 are hydrogen; R3, R4, R5, and R6, are independently chosen at each occurrence from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and T are both hydrogen (compounds of Formula IVb). Compounds of Formula IV particularly include compounds where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2 and R1, R2, R3, R4, R5, and R6 are all hydrogen (compounds of Formula IVc).
Preferred compounds of Formulas IV, and of IVa-IVc, are those where 
(xe2x80x9cArxe2x80x9d) represents phenyl, 2-pyrazinyl, or 2-pyridyl optionally substituted with Rp where Rp is C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino, or amino(C1-C6)alkyl. Preferably, Ar in Formula IV is phenyl, 2-pyridyl, or 2-pyrazinyl, each of which is optionally substituted with C1-C6 alkyl, or more preferably unsubstituted or substituted with methyl or ethyl. Still other preferred Ar groups in Formula IV are 3- and 4-pyrazolyl groups substituted in the 1-position with C1-C4 alkyl group, preferably methyl or ethyl.
In another embodiment the invention includes compounds of Formula V 
and the pharmaceutically acceptable salts thereof wherein the variables E, R1, R2, R3, R4, R5, R6, k, n, m, T, X, Q, W, and Z are as for Formula I. In a more specific embodiment, the invention includes compounds of Formula V where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2 and R1 and R2 are hydrogen (compounds of Formula Va). Still other compounds of Formula V are those compounds where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2; R1 and R2 are hydrogen; RA is C1-6alkyl, C1-C6 haloalkyl, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkyl, phenyl, thienyl, pyridyl, pyrimidinyl, or pyrrolyl; R3, R4, R5, and R6, are independently chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and T are both hydrogen (compounds of Formula Vb). In a still more specific embodiment the invention includes compounds of Formula V where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2, R1, R2, R3, R4, R5, and R6 are all hydrogen; and RA is methyl, ethyl, or pyridyl.
Yet another embodiment of the invention includes compounds of Formula VI 
and the pharmaceutically acceptable salts thereof, wherein the variables E, R1, R2, R4, R5, R6, k, n, m, T, X, Q, W, and Z are as defined for Formula I. Particular compounds of Formula VI are compounds where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2 and R1 and R2 are both hydrogen (compounds of Formula VIa). Other compounds of Formula VI are compounds where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2; and R1 and R2 are both hydrogen; R4, R5, and R6, are independently chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and T are both hydrogen (compounds of Formula VIb). A particular embodiment of the invention includes compounds of Formula VI where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2; and R1, R2, R5, R6, X and T are all hydrogen; and R4 is methyl (compounds of Formula VIc).
In still another embodiment, the invention provides compounds of Formula VII 
and the pharmaceutically acceptable salts thereof, wherein the variables E, R1, R2, RA, R4, R5, R6, k, n, m, T, X, Q, W, and Z are as defined for Formula I. Included as compounds of Formula VII are compounds where k is 2 and R1 and R2 are hydrogen (compounds of Formula VIIa). More particularly, the invention includes compounds of Formula VII where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2; R1 and R2 are hydrogen; RA is methyl, ethyl, or pyridyl; R4, R5, and R6, are independently chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and T are both hydrogen (compounds of Formula VIIb). The invention also particularly includes compounds of Formula VII where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2; R1, R2, R4, R5, R6, X and T are all hydrogen; and RA is methyl (compounds of Formula VIIc).
Further included as compounds of the invention are compounds of Formula VIII 
and the pharmaceutically acceptable salts thereof wherein the variables E, R1, R2, R4, R5, R6, k, n, m, T, X, Q, W, and Z are as defined as for Formula I. Such compounds of Formula VIII include compounds where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2 and R1 and R2 are both hydrogen (compounds of Formula VIIIa). In yet another embodiment the invention provides compounds of Formula VIII where k is 2; R1 and R2 are both hydrogen; R4, R5, and R6, are independently chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy; and X and T are both hydrogen (compounds of Formula VIIIb). More particularly, the invention provides compounds of Formula VIII where E is xe2x80x94(CR1CR2)kxe2x80x94, k is 2; R1, R2, R5, R6, X, and T are all hydrogen; and R4 is methyl (compounds of Formula VIIIc).
For each of Formula IIa, IIb, IIc, IIIa, IIIb, IIIc, IIId, IVa, IVb, IVc, Va, Vb, Vc, VIa, VIb, VIc, VIIa, VIIb, VIIc, VIIIa, VIIIb, and VIIIc the variables n, m, Q, W, and Z are as defined for Formula I.
Alternate embodiments of the invention include compounds of Formula IX, Formula X, Formula XI, and Formula XII (shown below) and the pharmaceutically acceptable salts thereof wherein variables R1, R2, R3, R4, R5, R6, k, n, m, T, X, Q, W, and Z are as defined for Formula I. 
Other compounds provided by the invention, but outside the definition of general Formula I, are compounds of the formula 
where Y is nitrogen, and all other variables are as defined for Formula I.
The invention also provides compounds of the formula B-1: 
where the xe2x80x9cB-ringxe2x80x9d is a 5-9 membered ring containing up to 4 hetero atoms selected from nitrogen, NRA, S, and oxygen. The B-ring is saturated, unsaturated or aromatic. All other variables are as defined for Formula I.
Preferred compounds of B-1 are those where the b-ring has the formula: 
wherein
R5a is hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, amino, mono- or di(C1-C6)alkylamino, or phenyl optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C1-C6)alkylamino.
Other preferred compounds of B-1 are those where the b-ring has the formula 
wherein
R5 and R6 carry the definitions given above with respect to Formula A or Formula I;
M is NRxe2x80x2 or oxygen; and
R5a and R5b are independently
hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, amino, or mono- or di(C1-C6)alkylamino, or
phenyl, pyridyl, phenyl(C1-C6)alkyl, or pyridyl(C1-C6)alkyl, where each phenyl and pyridyl is optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C1-C6)alkylamino; and
Rxe2x80x2 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy(C1-C6)alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C3-C6)alkyl, or
aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, where each aryl and heteroaryl is optionally substituted with up to 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- and di(C1-C6)alkylamino.
More preferred compounds of this group are those where
R5 and R6 are independently hydrogen or C1-C6 alkyl;
M is NRxe2x80x2 where Rxe2x80x2 is
hydrogen, C1-C6 alkyl, , C1-C6 alkoxy(C1-C6)alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or
aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, where each aryl and heteroaryl is optionally substituted with up to 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- and di(C1-C6)alkylamino; and
R5a and R5b are hydrogen.
Still other more preferred compounds of this group are those where
X and T are hydrogen; and
R3a and each R3 independently represent
hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- or di(C1-C6)alkylamino, C1-C6 alkyl, C1-C6 alkoxy, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, or
phenyl, pyridyl, pyrimidinyl, imidazolyl, or C1-C6 alkyl substituted with phenyl, pyridyl, or pyrimidinyl, or imidazolyl, where each phenyl, pyridyl, pyrimidinyl, and imidazolyl is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, and amino.
Yet other more preferred compounds of this group are those where Rxe2x80x2 is hydrogen, C1-C6 alkyl, or C1-C6 alkyl substituted with phenyl or pyridyl, where each phenyl or pyridyl is optionally substituted with halogen, hydroxy, amino, C1-C6 alkyl or C1-C6 alkoxy.
Particularly preferred compounds of this group are those where R5 and R6 are independently hydrogen or C1-C6 alkyl;
M is oxygen; and
R5a and R5b are hydrogen.
Also within formula B-1, there are included Formulas XIII and XIV. 
wherein
X, T, Q, n, W, m, and Z are as defined above with respect to Formula A or Formula I;
D is nitrogen or CR3 where
R3a and each R3 independently represents hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- or di(C1-C6)alkylamino, C1-C6 alkyl, C1-C6 alkoxy, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, aryl, heteroaryl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, cyano(C1-C6)alkyl, nitro(C1-C6)alkyl, or C1-C6 alkyl substituted with aryl or heteroaryl; and
R5a is hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, amino, mono- or di(C1-C6)alkylamino, or phenyl optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C1-C6)alkylamino.
In a specific aspect of Formula XIII, D is CR3 (hereinafter Formula XIII-a). Preferred compounds of XIII-a include those where each R3 is hydrogen, R5a and T are hydrogen, X is hydrogen or C1-C6 alkyl, preferably hydrogen or methyl, and R3a is C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, or hydroxy(C1-C6)alkyl. Particularly preferred R3a groups in Formula XIII-a are hydroxy, and more preferably, C1-C3 alkoxy.
In another specific aspect of Formula XIII, D is nitrogen (hereinafter Formula XIII-b). Preferred compounds of XIII-b include those where R3 is hydrogen, R5a and T are hydrogen, X is hydrogen or C1-C6 alkyl, preferably hydrogen or methyl, and R3a is C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, or hydroxy(C1-C6)alkyl.
Preferred compounds of Formulas XIII-a and XIII-b are those where 
(xe2x80x9cArxe2x80x9d) represents phenyl, pyrazolyl, or pyridyl, each of which is optionally substituted with Rp where Rp is C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino, or amino(C1-C6)alkyl. More preferably, Ar is 3- or4-pyrazolyl or 2- or 3-pyridyl, each of which is preferably substituted with C1-C6 alkyl, preferably methyl or ethyl, or more preferably unsubstituted. Particularly preferred Ar groups are 3-pyrazolyl and 2-pyridyl.
Preferred compounds of Formulas XIII-a and XIII-b are those where R5a is hydrogen.
Other preferred compounds of Formulas XIII-a and XIII-b are those where R5a is hydrogen;
X and T are hydrogen; and
R3a and each R3 independently represents
hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- or di(C1-C6)alkylamino, C1-C6 alkyl, C1-C6 alkoxy, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, cyano(C1-C6)alkyl, or nitro(C1-C6)alkyl, or
phenyl, pyridyl, pyrimidinyl, imidazolyl, or C1-C6 alkyl substituted with phenyl, pyridyl, or pyrimidinyl, or imidazolyl, where each phenyl, pyridyl, pyrimidinyl, and imidazolyl is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, and amino.
Still other preferred compounds of Formulas XIII-a and XIII-b are those where R5a is hydrogen;
R3 is hydrogen and R3a is hydrogen, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, amino or mono- or di(C1-C6)alkylamino.
Yet other preferred compounds of Formulas XIII-a and XIII-b are those where R5a is hydrogen; and R is hydrogen, C1-C6 alkoxy, hydroxy, or C1-C6 alkoxy.
As noted above, within formula B-1, there is included Formula XIV. 
wherein
X, T, Q, n, W, m, and Z are as defined above with respect to Formula A or Formula I;
M is NRxe2x80x2 or oxygen;
D is nitrogen or CR3 where
R3a and each R3 independently represents hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- or di(C1-C6)alkylamino, C1-C6 alkyl, C1-C6 alkoxy, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, aryl, heteroaryl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, cyano(C1-C6)alkyl, nitro(C1-C6)alkyl, or C1-C6 alkyl substituted with aryl or heteroaryl;
R5a and R5b are independently
hydrogen, hydroxy, halogen, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, amino, or mono- or di(C1-C6)alkylamino, or
phenyl, pyridyl, phenyl(C1-C6)alkyl, or pyridyl(C1-C6)alkyl, where each phenyl and pyridyl is optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C1-C6)alkylamino; and.
Rxe2x80x2 is
hydrogen, C1-C6 alkyl, C1-C6 alkoxy(C1-C6)alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or
aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, where each aryl and heteroaryl is optionally substituted with up to 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- and di(C1-C6)alkylamino.
In a specific aspect of Formula XIV, D is CR3 (hereinafter Formula XIV-a).
In another specific aspect of Formula XIV, D is nitrogen (hereinafter Formula XIV-b).
Preferred compounds of this group are those where
R5 and R6 are independently hydrogen or C1-C6 alkyl;
M is NRxe2x80x2 where Rxe2x80x2 is
hydrogen, C1-C6 alkyl, C2-C7 alkanoyl, C1-C6 alkoxy(C1-C6)alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or
aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, where each aryl and heteroaryl is optionally substituted with up to 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- and di(C1-C6)alkylamino; and
R5a and R5b are hydrogen.
Still other preferred compounds of this group of Formulas XIV-a and XIV-b are those where
X and T are hydrogen; and
R3a and each R3 independently represent
hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- or di(C1-C6)alkylamino, C1-C6 alkyl, C1-C6 alkoxy, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, or
phenyl, pyridyl, pyrimidinyl, imidazolyl, or C1-C6 alkyl substituted with phenyl, pyridyl, or pyrimidinyl, or imidazolyl, where each phenyl, pyridyl, pyrimidinyl, and imidazolyl is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, and amino.
Yet other preferred compounds of this group are those where each R3 is hydrogen and R3a is hydrogen, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, amino or mono- or di(C1-C6)alkylamino.
Still other preferred compounds within this group are those where R3a is hydrogen, C1-C6 alkoxy, hydroxy, or C1-C6 alkoxy.
Other preferred compounds within this group are those where R5a and R5b are hydrogen, C1-C6 alkyl, or C1-C6 alkyl substituted with phenyl or pyridyl, where each phenyl or pyridyl is optionally substituted with halogen, hydroxy, amino, C1-C6 alkyl or C1-C6 alkoxy.
Still other preferred compounds within this group are those where
R5 and R6 are independently hydrogen or C1-C6 alkyl;
M is oxygen; and
R5b and R5b are hydrogen.
Yet preferred compounds within this group are those wherein
X and T are hydrogen; and
R3a and each R3 independently represent
hydrogen, halogen, hydroxy, cyano, nitro, amino, mono- or di(C1-C6)alkylamino, C1-C6 alkyl, C1-C6 alkoxy, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, cyano(C1-C6)alkyl, or nitro(C1-C6)alkyl, or
phenyl, pyridyl, pyrimidinyl, imidazolyl, or C1-C6 alkyl substituted with phenyl, pyridyl, or pyrimidinyl, or imidazolyl, where each phenyl, pyridyl, pyrimidinyl, and imidazolyl is optionally substituted with one or two groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, and amino.
Still other preferred compounds within this group are those wherein each each R3 is hydrogen and R3a is hydrogen, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, amino or mono- or di(C1-C6)alkylamino.
Still other preferred compounds within this group are those where R3a is hydrogen, C1-C6 alkoxy, hydroxy, or C1-C6 alkoxy.
Preferred compounds of XIV-a (D is CR3) include those where M is NRxe2x80x2 where Rxe2x80x2 is hydrogen, C1-C6 alkyl, preferably C1-C3 alkyl, each R3 is hydrogen, R5a R5b, and T are hydrogen, X is hydrogen or C1-C6 alkyl, preferably hydrogen or methyl, R5 and R6 are independently hydrogen or C1-C2 alkyl, more preferably hydrogen or methyl, and R3a is C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, or hydroxy(C1-C6)alkyl. Preferred R3a groups in Formula XIV-a are hydroxy and C1-C3 alkoxy. Particularly preferred Rxe2x80x2 groups are
Other preferred compounds of XIV-b (D is nitrogen) include those where M is NRxe2x80x2 where Rxe2x80x2 is hydrogen or acetyl, R3 is hydrogen, R5a, R5b, and T are hydrogen, X is hydrogen or C1-C6 alkyl, preferably hydrogen or methyl, and R3a is C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, or hydroxy(C1-C6)alkyl.
Preferred compounds of Formulas XIV-a and XIV-b are those where 
(xe2x80x9cArxe2x80x9d) represents phenyl, pyrazolyl, or pyridyl, each of which is optionally substituted with Rp where Rp is C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, amino, or amino(C1-C6)alkyl. More preferably, Ar is 3- or4-pyrazolyl or 2- or 3-pyridyl, each of which is preferably substituted with C1-C6 alkyl, preferably methyl or ethyl, or more preferably unsubstituted. Particularly preferred Ar groups are 3-pyrazolyl and 2-pyridyl.
Further provided by the invention are intermediates useful in synthesizing compounds of the invention. Thus, the invention encompasses compounds of the following formulas 
wherein
the A-ring, Y, V, E, R5, R6, X and T carry the definitions assigned with respect to Formula A; and
RB is a group forming an ester, e.g., C1-C6 alkyl, aryl(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkyl, and the like.
Preferred RB groups are hydrogen, methyl, ethyl and benzyl.
Specific compounds of Formula XV include those where U is nitrogen, NRA, S, or O; V is nitrogen, carbon or CH; and Y is carbon, or CH;
Preferred compounds of Formula XV are those where the A-ring represents 
Preferred RA, R3, and R4 groups on compounds of Formula XV are hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy.
Preferred compounds of XV include those of Formulas XVI and XVII. 
wherein:
R4 is chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy. 
wherein:
RA is chosen from hydrogen, methyl, ethyl, and phenyl; and 
wherein:
R3 is hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, or ethoxy.
The invention encompasses compounds of Formulas I-1, I-2, I-3, I-4, and I-5. 
wherein:
A is oxygen or sulfur;
E, R5, R6, and T carry the definition assigned with respect to Formula I and Formula A; and
RB is a group forming an ester, e.g., C1-C6 alkyl, aryl(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, C1-C6 alkoxy(C1-C6)alkyl, and the like.
Preferred RB groups are hydrogen, methyl, ethyl and benzyl. 
wherein
B is xe2x80x94SCH3 or xe2x80x94NH(CH2)CH(OCH3)2; and
RB is chosen from hydrogen, methyl, ethyl and benzyl. 
wherein
E, R5, R6, and T carry the definition assigned with respect to Formula I and Formula A; and
R3 and R4 independently carry the same definitions as R5 and R6; and
RB is chosen from hydrogen, methyl, ethyl and benzyl. 
wherein:
E, X, R5, R6, and T carry the definition assigned with respect to Formula I and Formula A; and
RB is chosen from hydrogen, methyl, ethyl and benzyl. 
wherein:
E, R5, R6, and T carry the definition assigned with respect to Formula I and Formula A; and
R3 is defined the same as R5 and R6; and
RB is chosen from hydrogen, methyl, ethyl and benzyl;
RC is independently chosen at each occurrence from t-butoxycarbonyl, phenyl, phenylsulfonyl, C1-C6 alkylsulfonyl, and ethylcarbamoyl.
Each of the synthetic schemes provided in the xe2x80x9cPreparation of Compoundsxe2x80x9d section (below) involves the reaction of a ester compound to form an amide. For example, see step 11 of Scheme 1. Thus, the invention provides ester intermediates of Formula XX 
wherein
E and J carry the definitions assigned with respect to Formula A and Formula I;
R1 and R2 are independently chosen at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, amino, alkyl, alkenyl, alkynyl, haloalkyl, and mono or dialkylamino, mono or dialkylaminoalkyl, alkoxy, and k is 0, 1, 2, or 3;
the group 
xe2x80x83referred to as the xe2x80x9cA-ringxe2x80x9d represents an optionally substituted saturated, unsaturated or aromatic heterocyclic ring containing at least one nitrogen, oxygen or sulfur atom, wherein the VY bond is a single, double, or aromatic bond;
V is nitrogen, carbon, or CH;
Y is carbon, or CH;
R5 and R6 may be taken together to form a carbonyl group; or
R5 and R6 are independently chosen from hydrogen, halogen, hydroxy, nitro, cyano, alkyl1, amino, xe2x80x94COOH, xe2x80x94O(alkyl1), xe2x80x94SO2NH2, xe2x80x94SO2NH(alkyl1), xe2x80x94SO2N(alkyl1)(alkyl1), xe2x80x94N(alkyl1)CO(alkyl1), N(alkyl1)CO2(alkyl1), xe2x80x94NHSO2(alkyl1), xe2x80x94N(alkyl1)SO2(alkyl1), xe2x80x94SO2NHCO(alkyl1), xe2x80x94CONHSO2(alkyl1), xe2x80x94CONH(alkyl1), xe2x80x94CON(alkyl1)(alkyl1), xe2x80x94CO2(alkyl1), xe2x80x94CO(alkyl1), xe2x80x94SO0-2(alkyl1), optionally substituted carbocyclic aryl and optionally substituted heteroaryl groups having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
wherein alkyl1 is independently chosen at each occurrence and is straight branched or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy, xe2x80x94COOH, xe2x80x94SO2NH2, xe2x80x94SO2NH(alkyl), xe2x80x94SO2N(alkyl)(alkyl), xe2x80x94N(alkyl)CO(alkyl), N(alkyl)CO2(alkyl), xe2x80x94NHSO2(alkyl), xe2x80x94N(alkyl)SO2(alkyl), xe2x80x94SO2NHCO(alkyl), xe2x80x94CONHSO2(alkyl), xe2x80x94CONH(alkyl), xe2x80x94CON(alkyl)(alkyl), xe2x80x94CO2(alkyl), xe2x80x94CO(alkyl) xe2x80x94SO0-2(alkyl)
X is chosen from hydrogen, hydroxy, amino, alkyl, and alkoxy;
T is chosen from hydrogen, halogen, hydroxy, amino, alkyl, and alkoxy; and
RB is chosen from hydrogen, methyl, ethyl and benzyl.
Preferred compounds of Formula XX include compounds wherein E is xe2x80x94(CR1R2)kxe2x80x94, xe2x80x94CR1xe2x95x90CR2xe2x80x94, xe2x80x94Nxe2x95x90CR1xe2x80x94, or xe2x80x94NRxe2x80x2xe2x80x94(CR1R2)kxe2x80x94. Particularly preferred are xe2x80x94(CR1R2)kxe2x80x94, xe2x80x94Nxe2x95x90CR1xe2x80x94, and xe2x80x94NRxe2x80x2xe2x80x94(CR1R2)kxe2x80x94.
Other preferred compounds of Formula XX are those where J is xe2x80x94(CR5R6)dxe2x80x94 where d is 1.
Still other preferred compounds of Formula XX are those where E is xe2x80x94Nxe2x95x90CR1xe2x80x94 and d is 0, or xe2x80x94NRxe2x80x2xe2x80x94(CR1R2)kxe2x80x94 where d is 0 and k is 1.
Preferred compounds of Formula XX include compounds wherein
E and J carry the definitions given with respect to Formulas A and I;
R1 and R2 are independently chosen at each occurrence from hydrogen, halogen, hydroxy, cyano, nitro, amino, haloalkyl, mono or diamino(C1-6)alkyl, C1-6 alkyl, C2-6alkenyl, C2-6alkynyl and C1-6 alkoxy, and k is 0, 1, 2, or 3;
the group 
or the xe2x80x9cA-ringxe2x80x9d is a group of the formula: 
xe2x80x83which is a saturated, unsaturated or aromatic heterocyclic ring containing at least one nitrogen, oxygen or sulfur atom, wherein the UY and VY bonds may be single, double or aromatic bonds,
U is nitrogen, NRA, S, or O;
V is nitrogen, carbon or CH;
Y is carbon, or CH;
and said saturated, unsaturated or aromatic heterocyclic ring is chosen from:
thienyl, thiazolyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, pyrazinyl, pyridizinyl, piperidinyl, oxazolyl, isoxazolyl, symmetrical and unsymmetrical triazolyl, pyrrolyl, furanyl, diazenyl, triazenyl, 1,2,4-triazolone, 4,5-dihydroimidazolyl, and 1,4,5,6-tetrahydropyrimidinyl,
each of which is optionally substituted at any available nitrogen by RA and optionally substituted at any available carbon by R3 and R4, wherein:
RA is chosen from hydrogen, C1-6alkyl1, optionally substituted carbocyclic aryl and optionally substituted heteroaryl groups having from 1 to 3 rings, 3 to 8 members in each ring and from 1 to 3 heteroatoms;
R5 and R6 are independently chosen from hydrogen, halogen, hydroxy, nitro, cyano, C1-6alkyl1, amino, xe2x80x94COOH, xe2x80x94O(C1-6alkyl1), xe2x80x94NH(C1-6alkyl1), xe2x80x94N(C1-6alkyl1)(C1-6alkyl1), xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-6alkyl1), xe2x80x94SO2N(C1-6alkyl1)(C1-6alkyl1), xe2x80x94N(C1-6alkyl1)CO(C1-6alkyl1)N(C1-6alkyl1)CO2(C1-6alkyl1) NHSO2(C1-6alkyl1), xe2x80x94N(C1-6alkyl1) SO2(C1-6alkyl1), xe2x80x94SO2NHCO(C1-6alkyl1), xe2x80x94CONHSO2(C1-6alkyl1), xe2x80x94CONH(C1-6alkyl1), xe2x80x94CON(C1-6alkyl1)(C1-6alkyl1), xe2x80x94CO2(C6alkyl1), xe2x80x94CO(C1-6alkyl1) and xe2x80x94SO0-2(C1-6alkyl1),
wherein C1-6alkyl1 is independently chosen at each occurrence and is straight branched or cyclic, may contain one or two double or triple bonds, and is unsubstituted or substituted with one or more substituents selected from: hydroxy, oxo, halogen, amino, cyano, nitro, alkoxy, carbocylic or heterocyclic group, xe2x80x94COOH, xe2x80x94SO2NH2, xe2x80x94SO2NH(C1-4alkyl), xe2x80x94SO2N(C1-4alkyl)(C1-4alkyl), xe2x80x94N(C1-4alkyl)CO(C1-4alkyl), N(C1-4alkyl)CO2(C1-4alkyl), xe2x80x94NHSO2(alkyl), xe2x80x94N(C1-4alkyl) SO2(C1-4alkyl), xe2x80x94SO2NHCO(C1-4alkyl), xe2x80x94CONHSO2(C1-4alkyl), xe2x80x94CONH(C1-4alkyl), xe2x80x94CON(C1-4alkyl)(C1-4alkyl) xe2x80x94CO2(C1-4alkyl), xe2x80x94CO(C1-4alkyl), and xe2x80x94SO0-2(C1-4alkyl);
R3 and R4 are independently chosen at each occurrence, and are defined the same as R5 and R6;
X is chosen from hydrogen, hydroxy, amino, C1-6 alkyl, and C1-6alkoxy;
T is chosen from hydrogen, halogen, hydroxy, amino, C1-6 alkyl, and C1-6 alkoxy; and
RB is chosen from hydrogen, methyl, ethyl and benzyl.
Such compounds will be referred to as compounds of Formula XXa.
The ester intermediates of this invention differ primarily in the type of xe2x80x9cA-ringxe2x80x9d present although other differences may be present. one class of intermediates provided by this invention is represented by Formula XXI 
wherein J, E, R1, R2, R3, R4, R5, R6, J, E, k, X, T, and RB are as defined for Formula XXa. Preferred intermediates of Formula XXI are those compounds wherein RB is defined as for Formula XXa; E is xe2x80x94(CR1R2)kxe2x80x94, k is 1 or 2; R1 and R2 are both hydrogen; and R3, R4, R5, and R6, are independently chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy (hereinafter compounds of Formula XXIa).
The invention further provides ester intermediates having a pyridyl xe2x80x9cA-ringxe2x80x9d such as compounds of Formula XXII 
wherein R3 is independently selected at each occurrence and is as defined as for Formula XXa and R1, R2, R3, R4, R5, E, J, k, X, T, and RB are also defined as for Formula XXa.
Particularly, the invention provides as compounds of Formula XXII, compounds where RB is defined as for Formula XXa; E is xe2x80x94(CR1R2)kxe2x80x94; R1, R2, R3, R5, R6, X, and T are all hydrogen; R3 is hydrogen at the 3- and 4-positions of the xe2x80x9cA-ringxe2x80x9d pyridyl group, and is chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy at the 2-position of this xe2x80x9cA-ringxe2x80x9d pyridyl group (hereinafter compounds of Formula XXIIa).
Also provided as compounds of Formula XXII, are compounds where E is xe2x80x94(CR1R2)kxe2x80x94; RB is defined as for Formula XXa; R1, R2, R3, R5, R6, X, and T are all hydrogen; R3 is hydrogen at the 2- and 4-positions of the xe2x80x9cA-ringxe2x80x9d pyridyl group, and is chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy at the 3-position of this xe2x80x9cA-ringxe2x80x9d pyridyl group (hereinafter compounds of Formula XXIIb).
The invention provides intermediates of Formula XXIII having a pyrimidinyl xe2x80x9cA-ringxe2x80x9d 
wherein R1, R2, R3, R4, R5, R6, E, k, X, T, and R are as defined in claim XXa. Preferred compounds of Formula XXIII include compounds where E is xe2x80x94(CR1R2)kxe2x80x94; k is 2; R1, R2, R3, R5, R6, X, and T are all hydrogen; RB is defined as for Formula XXa; and R4 is chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy (hereinafter compounds of Formula XXIIIa).
In one embodiment the invention provides compounds of Formula XXIV where the xe2x80x9cA-ringxe2x80x9d is a pyrrole 
wherein RA, R1, R2, R4, R5, R6, E, k, X, T, and RB are as defined in Formula XXa. Preferred compounds of Formula XXIV include compounds where E is xe2x80x94(CR1R2)kxe2x80x94; k is 2; RA is chosen from hydrogen, methyl, ethyl, and phenyl; RB is as defined in Formula XXa; and R1, R2, R4, R5, R6, X, and T are all hydrogen (hereinafter compounds of Formula XXIVa).
The invention further includes compounds of Formula XXV 
wherein RA, R1, R2, R3, R4, R5, R6, E, k, X, T, and RB are as defined for Formula XXa. Also included as compounds of Formula XXV are compounds wherein E is xe2x80x94(CR1R2)kxe2x80x94; k is 2; RA, R1, R2, R4, R5, R6, k, X, and T are all hydrogen; RB is as defined for Formula XXa; and R4 is from chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy (hereinafter compounds of Formula XXVa).
In yet another embodiment the invention provides ester intermediates of Formula XXVI having thiazole xe2x80x9cA-ringsxe2x80x9d
wherein R1, R2, R3, R5, R6, E, k, X, T, and RB are as defined for Formula XXa. Preferably compounds of this class are those compounds where E is xe2x80x94(CR1R2)kxe2x80x94; k is 2; R1, R2, R5, R6, X, and T are hydrogen; RB is as defined for Formula XXa; and R3 is chosen from R3 is chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy (hereinafter compounds of Formula XXVIa).
Another class of intermediates of the invention is represented by compounds of Formula XXVII having and isoxazole xe2x80x9cA-ringxe2x80x9d
wherein R1, R2, R3, R5, R6, E, k, X, T, and RB are as defined in for Formula XXa. Preferably compounds of this class are those compounds where E is xe2x80x94(CR1R2)kxe2x80x94; k is 2; R1, R2, R5, R6, X, and T are hydrogen; R3 is as defined for Formula XXa; and R3 is chosen from R3 is chosen from hydrogen, halogen, amino, hydroxy, methyl, ethyl, methoxy, and ethoxy (hereinafter compounds of Formula XXVIIa).
In a number of the synthetic steps used to generate compounds of the invention novel protected intermediates are used. Such protected intermediates include compounds of Formula XXX useful in the synthesis of compounds of the invention having an imidazole xe2x80x9cA-ringxe2x80x9d
wherein A is oxygen or sulfur; J, E, k, R1, R2, R5, R6, RB and T are as defined for Formula XXa. Preferably, E is xe2x80x94(CR1R2)kxe2x80x94; and d is 1 or 2, more preferably 1.
Another class of protected intermediates useful in the synthesis of compounds of the invention having an imidazole xe2x80x9cA-ringxe2x80x9d are compounds of Formula XXXI 
wherein B is xe2x80x94SCH3 or xe2x80x94NH(CH2)CH(OCH3)2 and J, E, k, R1, R2, R5, R6, RB and T are as defined for Formula XXa. Preferably, E is xe2x80x94(CR1R2)kxe2x80x94; and d is 1 or 2, more preferably 1.
Also provided are compounds of Formula XXXII 
wherein all variables present in compounds of Formula XXXII are defined as for compounds of Formula XXa. Preferably, E is xe2x80x94(CR1R2)kxe2x80x94; and d is 1 or 2, more preferably 1.
Other classes of novel intermediates provided by the invention are intermediates have BOC and TMS protecting groups (or analogues of such groups) such as compounds of Formula XXXIII 
wherein RC is chosen from t-butoxycarbonyl, phenyl, alkylsulfonyl, and ethylcarbamoyl; RZ is hydrogen or bromo; and J, E, k, RB, R1, R2, R5, R6, and T are defined as for compounds of Formula XXa.
Preferably, E is xe2x80x94(CR1R2)kxe2x80x94; and d is 1 or 2, more preferably 1.
Further provided are compounds of Formula XXXIV 
RC is chosen from t-butoxycarbonyl, phenyl, phenylsulfonyl, alkylsulfonyl, and ethylcarbamoyl;
RD is chosen from trimethylsilyl and t-butyldimethylsilyl; and
J, E, k, RB, R1, R2, R5, R6, and T are defined as for Formula XXa.
Preferably, E is xe2x80x94(CR1R2)kxe2x80x94; and d is 1 or 2, more preferably 1.
Further, the invention provides as intermediates compounds of Formula XXXV 
wherein E, J, k, RB, R1, R2, R5, R6, X and T are as defined for Formula XXa. In compounds of XXXV, E is preferably xe2x80x94(CR1R2)kxe2x80x94 and d is 1 or 2, more preferably 1.
Finally, the invention provides compounds of Formula XXXVI as intermediates 
RC is independently chosen at each occurrence from t-butoxycarbonyl, phenyl, phenylsulfonyl, alkylsulfonyl, and ethylcarbamoyl and all other variables are as defined for compounds of Formula XXa.
In preferred compounds of XXXVI, Preferably, E is preferably xe2x80x94(CR1R2)kxe2x80x94 and d is 1 or 2, more preferably 1.
This invention relates to heterocyclic compounds, such as 5,6-Dihydro-4H-1,3a,6-triaza-as-indacenes,3-thia-1,7-diaza-cyclopenta[e]azulene-9-carboxylic acids, 4,5,6,7-tetrahydro-1-oxa-2,7-diaza-cyclopenta[e]azulene -9-carboxylic acids, 3,8,10-triaza-benzo[e]azulene-1-carboxylic acids, 1-oxa-2,7-diaza-cyclopenta[e]azulene-9-carboxylic acids, 1,3,7-triaza-cyclopenta[e]azulene-9-carboxylic acid phenyl amide and related compounds, that bind with high affinity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. This invention also includes such compounds that bind with high selectivity to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds.
The invention further comprises methods of treating patients in need of such treatment with an amount of a compound of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the inventions that act as agonists at xcex12xcex23xcex32 and xcex13xcex23xcex32 receptor subtypes are useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress, and acute stress disorders. Compounds of the inventions that act as agonists at xcex12xcex23xcex32 and xcex13xcex23xcex32 receptor subtypes are also useful in treating depressive or bipolar disorders and in treating sleep disorders. Compounds of the invention that act as inverse agonists at the xcex15xcex23xcex32 receptor subtype or xcex11xcex22xcex32 and xcex15xcex23xcex32 receptor subtypes are useful in treating cognitive disorders including those resulting from Down Syndrome, neurodegenerative diseases such as Alzheimer""s disease and Parkinson""s disease, and stroke related dementia. Compounds of the invention that act as agonists at the xcex11xcex22xcex32 receptor subtype are useful in treating convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and in treating drug and alcohol addiction.
The diseases and/or disorders that can also be treated using compounds and compositions according to the invention include:
Depression, e.g. depression, atypical depression, bipolar disorder, depressed phase of bipolar disorder.
Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic disorder +/xe2x88x92 agoraphobia, social phobia, specific phobia, Post traumatic stress disorder, obsessive compulsive disorder (OCD), dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders, cyclothymia.
Sleep disorders, e.g. sleep disorders including primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, substance induced sleep disorder.
Cognition Impairment, e.g. cognition impairment, Alzheimer""s disease, Parkinson""s disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis.
Attention Deficit Disorder, e.g. Attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD)
The invention also provides pharmaceutical compositions comprising one or more compounds of the invention together with at least one pharmaceutically acceptable carrier. Pharmaceutical compositions include packaged pharmaceutical compositions for treating disorders responsive to GABAA receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABAA receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABAA receptor ligand is to be used for treating a disorder responsive to GABAA receptor modulation in the patient.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer""s dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.
Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a]phthalzine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3-b]pyridazines, in combination with SSRIs.
The present invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as Ro15-1788, to the GABAA receptors which methods involve contacting a compound of the invention with cells expressing GABAA receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding to GABAA receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula A or Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds to GABAA receptors in vitro. In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABAA receptor may be readily determined via a GABAA receptor binding assay, such as the assay described in Example 24. The GABAA receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABAA receptors.
The present invention also pertains to methods for altering the signal-transducing activity, particularly the chloride ion conductance of GABAA receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula A or Formula I that would be sufficient to alter the signal-transducing activity of GABAA receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABAA receptors may be determined via a GABAA receptor signal transduction assay, such as the assay described in Example 25.
The GABAA receptor ligands provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the GABAA receptor.
Labeled derivatives the GABAA receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
For compounds of the present invention that have The compounds of the invention may have asymmetric centers; this invention includes all of the stereoisomers and optical isomers as well as mixtures thereof.
In addition, compounds with carbon-carbon double bonds may occur in Zxe2x80x94 and Exe2x80x94 forms; all such isomeric forms of the compounds are included in the invention.
When any variable (e.g. C1-6 alkyl, R1, R2, R5, and R6) occurs more than one time in any formula herein, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the terms xe2x80x9calkylxe2x80x9d and xe2x80x9cCy-x alkylxe2x80x9d in the present invention is meant straight or branched chain alkyl groups of generally up to 6 or 8 carbon atoms, or for Cy-x alkyl the number of carbon atoms specified, for example, C1-6 alkyl indicates straight or branched chain alkyl groups having from 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. Preferred C1-8 alkyl groups are methyl, ethyl, propyl, butyl, pentyl and cyclopentyl.
As used herein, xe2x80x9calkanoylxe2x80x9d refers to an alkyl group as defined above attached through a carbonyl bridge. Examples include acetyl, propionyl, and butyryl.
The term xe2x80x9calkoxyxe2x80x9d represents an alkyl group, as described above, attached through an oxygen bridge, such as methoxy, ethoxy, propoxy and isopropoxy.
The term xe2x80x9calkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl.
The term xe2x80x9calkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration comprising one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl.
As used herein, xe2x80x9ccarbocyclic groupxe2x80x9d refers to aromatic carbocyclic ring systems and to cycloalkyl ring systems that have one or more double or triple bonds.
The term xe2x80x9carylxe2x80x9d is used to indicate aromatic groups that contain only carbon atoms in the ring structure. Thus, the term xe2x80x9carylxe2x80x9d refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups are, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl. The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such aryl groups are optionally substituted with, for example, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl,.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to saturated ring groups, having the specified number of carbon atoms, e.g., C3-C7 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain situations, the cycloalkyl group will contain one or more double or triple bonds and may be substituted with one or more substituents such as C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl, aryl and heteroaryl. Cycloalkyl groups herein that lack any unsaturation are referred to as saturated cycloalkyl groups while cycloalkyl groups that contain at least one double or triple bond but are not aromatic are referred to as either unsaturated or partially unsaturated.
The term xe2x80x9ccycloalkylalkylxe2x80x9d refers to cycloalkyl groups as defined above attached to an alkyl group. Generally, the cycloalkyl group will contain from 3-7 carbon atoms and the alkyl portion will contain from 1-8, more preferably, 1-6, carbon atoms. These cycloalkylalkyl groups are identified herein as C3-C7 cycloalkyl(C1-C6)alkyl groups. Examples of such groups are cyclopropylmethyl, cyclohexylmethyl, and cyclohexylmethyl.
The term xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. Preferred haloalkyl groups are halo(C1-C6)alkyl groups; particularly preferred are trifluoromethyl, perfluoropropyl, and difluoromethyl.
By xe2x80x9chaloalkoxyxe2x80x9d as used herein is meant represents a haloalkyl group, as defined above, attached through an oxygen bridge to a parent group. Preferred haloalkoxy groups are halo(C1-C6)alkoxy groups. Examples of haloalkoxy groups are trifluoromethoxy, 2,2-difluoroethoxy, 2,2,3-trifluoropropoxy and perfluoroisopropoxy.
As used herein, the group xe2x80x9cVYxe2x80x9d represents V and Y connected by a single or double bond. Similarly, the groups xe2x80x9cUYxe2x80x9d and xe2x80x9cVYxe2x80x9d represent single or double bonds connecting U and Y and V and Y respectively. In specific embodiments, where these groups are double bonds, they give rise to aromatic groups.
The term xe2x80x9cheterocycloalkanonexe2x80x9d refers to 4-, 5-, 6- and 7-membered ring systems having at least one hetero atom selected from oxygen, nitrogen, and sulfur and also having at least one oxo group, i.e., the ring contains a carbonyl group. Such heterocycloalkanone groups are optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, hydroxy, halogen, amino, mono- or di(C1-C6)alkylamino, and the like. Examples include 
As used herein, the terms xe2x80x9cheterocyclic groupxe2x80x9d or xe2x80x9cheterocycloalkylxe2x80x9d are intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 hetero atoms independently selected from N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur hetero atoms may optionally be oxidized. The term xe2x80x9cheteroarylxe2x80x9d is used to specifically indicate aromatic heterocyclic groups.
The heterocyclic ring may be attached to its pendant group at any hetero atom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these hetero atoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 hetero atoms independently selected from N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benoztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;-1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.
Where an aryl, cycloalkyl, heterocycloalkyl, or heteroaryl is substituted with oxo, the resulting groups will have an oxygen atom connected to a ring within the system by a double bond. Examples of such oxo substiuted systems include 2-oxo-1,2-dihydro-pyridin-3-yl and 2-oxo-1,2-dihydro-pyridin-4-yl groups. Such groups have the formulas 
These groups may be substituted on any of the ring carbon atoms or the ring nitrogen, with various substituents as specified herein.
The term xe2x80x9chalogenxe2x80x9d indicates fluorine, chlorine, bromine, and iodine.
Non-toxic xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d include, but are not limited to salts with inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrite or salts with an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, salicylate and stearate. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. The present invention also encompasses the prodrugs of the compounds of Formula I.
Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
For administration to non-human animals, the composition may also be added to the animal feed or drinking water. It will be convenient to formulate these animal feed and drinking water compositions so that the animal takes in an appropriate quantity of the composition along with its diet. It will also be convenient to present the composition as a premix for addition to the feed or drinking water.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocyctes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcovxc3xa1, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).
A general illustration of the preparation of compounds of Formula I in the present invention is given in Schemes 1-12. In the reaction schemes and discussions that follow, unless otherwise indicated, k, RA, R1, R2, R3, R4, R5, R6 are as defined above. Within the schemes and tables that follow, Ar is intended to represent Qxe2x80x94(CH2)nxe2x80x94Wxe2x80x94(CH2)mxe2x80x94Z as defined in Formula I or a suitably protected form thereof. When a protecting group is required, an optional deprotection step may be employed. Suitable protecting groups and methodology for protection and deprotection such as those described in Protecting Groups in Organic Synthesis by T. Greene are well known and appreciated in the art. Compounds and intermediates requiring protection/deprotection will be readily apparent to those skilled in the art. 
In Scheme 1 step 1, p-nitrophenethylamine is alkylated with tert-butyl bromo acetate to form compound (2). In general, excess p-nitrophenethylamine is used in this reaction to minimize bis-alkylation. In step 2, the secondary amine in compound (2) is coupled with BOC-protected 3-aminopropanoic acid to form compound (3). This coupling may be efficiently accomplished by treating a mixture of compound (2) in pyridine with N-Boc 3-aminopropanoic with a coupling agent such as EDCI with stirring at ambient temperature. In step 3, the tert-butyl ester in compound (3) is cleaved under basic conditions to form the carboxylic acid (4). Compound (4) is reacted with dimethyl acetylene dicarboxylate in the presence of acetic anyhydride in step 4 to form the pyrrole (5). Pyrrole (5) is sequentually deprotected using hydrogen chloride in step 5 to expose the primary amine in compound (6) and cyclized in the presence of base to form lactam (7). In step 6, lactam (7) is converted to the thiolactam (8) by reaction under appropriate sulfur transfer conditions such as heating with P4S10 in pyridine. In steps 7 and 8, thiolactam (8) is alkylated with methyl iodide in acetone to form the methylsulfanyl compound (9) which is reacted with aminoacetaldehyde dimethyl acetal in methanol to form compound (10). Cyclization of the dimethyl acetal derivative (10) is accomplished in step 9 by heating (10) with concentrated hydrochloric acid in methanol to form compound (11). Removal of the p-nitrophenethyl protecting group is accomplished in step 10 by treatment of (11) with sodium hydride in the presence of di-tert-butyl dicarbonate in dimethylformamide. Quenching of excess sodium hydride with acetic acid followed by hydrolysis of the BOC group from the pyrrole nitrogen using aqueous potassium bicarbonate provides the desired deprotected material (12). As indicated by step 11 in Scheme 1, ester (12) serves as a versatile acylating agent for a variety of aluminum complexes of aryl and heteroaryl amines to form the corresponding amides (13).
Another procedure for forming amide derivatives (13) is provided in Example 2a and involves hydrolysis of ester (12) by heating in the presence of 48% hydrobromic acid. The resulting carboxylic acid is then reacted with various aryl amines in the presence of an appropriate coupling reagent such as O-(1H-benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate. Alternatively, the carboxylic acid may be converted to the mixed anhydride by reaction with ethyl or isobutyl chloroformate in the presence of triethylamine. The resulting mixed anhydride is then reacted with aryl amines.
Compounds of Formula II where R5 or R6 is methyl are formed as illustrated in Scheme 1 by reaction of compound (2) with 3-aminobutyric acid in step 2. Optically pure or optically enriched material is obtained by separation of advanced intermediates on a suitable chiral HPLC column such as Chiralpak AD. For material resolved by this method, the absolute stereochemistry is correlated to a X-ray crystal structure of a chiral amide derivative. Alternatively, optically pure 3-aminobutyric acid may be employed in step 2. Compounds of Formula II wherein both R5 and R6 are methyl are obtained as illustrated in Scheme 1 by use of 3-amino-3-methylbutyric acid in step 2.
Compounds of Formula II wherein R3 is methyl may be formed as illustrated by Scheme 1 by employing 2-aminopropionaldehyde dimethyl acetal in step 8.
Those skilled in the art will realize that the synthetic transformations described by Scheme 1 may be accomplished using a variety of alternate reagents and reaction conditions. Further, it is readily apparent that additional compounds within the scope of Formula II but not specifically described within the experimental section may be prepared in analogous fashion. 
Scheme 2 reveals a method for converting known ketone (14) (U.S. Pat. No. 5,723,462, col.23-31 is hereby incorporated by reference for its teachings regarding the synthesis of such ketones) to compounds of Formula III with R3 as methyl. Step 1 describes formation of the BOC-protected derivative (15). Typically this transformation is carried out by treating pyrrole (14) with di-tert-butyl dicarbonate in a suitable solvent such as dichloromethane or 1,4-dioxane at temperatures ranging from 0xc2x0 C. to ambient temperature in the presence of an organic base such as triethylamine. Additives such as 4-N,N-dimethylaminopyridine may be used to facilitate this transformation. In step 2, the BOC-protected material (15) is efficiently converted to silyl enol ether (16) by treatment with a mixture of trimethylsilyl chloride, sodium iodide and triethylamine at ambient temperature. Lewis acid-facilitated 1,4-addition is accomplished in step 3 by treatment with excess methyl vinyl ketone at 0xc2x0 C. in the presence of zinc chloride-alumina to yield the diketone (17). Treatment of the diketone (17) with ammonium acetate at elevated temperature in step 4 provides the desired methyl-substituted pyridyl derivative (18) which is aminated in step 5 using amination conditions previously described for Scheme 1. 
Scheme 3 shows a method for converting known ketone (14) [U.S. Pat. No. 5,723,462] to compounds of Formula III with R3 as hydrogen. In step 1, pyridine ring formation is accomplished by treatment of ketone (14) with 3-aminoacrolein (Rxe2x95x90H) and catalytic ammonium acetate in triethylamine at elevated temperature. Conversion of (14) to (20) can also be accomplished by heating (14) in triethylamine with 3-dimethylaminoacrolein in the presence of excess ammonium acetate. If 3-amino-2-methylacrolein (Rxe2x95x90CH3) is used in step 1, a 3-methylpyridine ring is formed. Amination is accomplished in step 2 as previously described.
Those skilled in the art will recognize that the reactions described in Scheme 3 may also be applied to synthesize compounds of Formula III wherein k=1 by starting with the appropriate known ketone. 
Scheme 4 outlines conditions for conversion of ketone (15) to compounds of Formula IV. In step 1, ketone (15) is reacted with tris(dimethylamino)methane with heating in a sealed tube to afford compound (22). In step 2, compound (22) undergoes reaction with formamidine acetate in ethanol at 120xc2x0 C. to yield the pyrimidine derivative (23). As shown in step 3, compound (23) serves as a versatile intermediate for reaction with aluminum complexes of a variety of aryl amines under conditions previously described. 
Scheme 5 describes a method for producing compounds of Formula IV wherein R4 is methyl. Reaction of compound (16) from Scheme 2 with acetyl chloride in the presence of catalytic sodium iodide and a suitable Lewis acid such as bismuth trichloride gives diketone (25). Subsequent reaction with formamidine acetate as per Scheme 4, provides methyl pyrimidine (26) which is aminated in step 3 as previously described. 
Scheme 6 provides a means of obtaining compounds of Formula V. In step 1, compound (22) from Scheme 4 is reacted with methylhydrazine (RAxe2x95x90CH3) in ethanol at 120xc2x0 C. to obtain approximately a 3:1 mixture of compounds (28) and (29). The structure of compound (28) is assigned based on X-ray crystal analysis. After separation by chromatography on silica gel, compound (28) is converted to amide derivatives in step 2 as previously described. Compound (29) may likewise be reacted. Reaction of (22) with hydrazine acetate as shown in step la provides a pyrazole ring with a free NH. To improve the handling characteristics of this material, it is BOC-protected by means of reaction with di-tert-butyl dicarbonate in the presence of triethylamine to give compound (31). Compound (31) can be converted to amide derivatives (32) as shown in step 2a using previously described conditions.
Compounds of Formula V, wherein RA is a substituted aminoethyl substituent, may be prepared as shown in step 3. Compound (28) (RAxe2x95x90CH2CH2OH), which is prepared as shown in step 1 by the reaction of (22) with 2-hydroxyethylhydrazine, is converted to the corresponding mesylate using standard conditions, such as methanesulfonyl chloride in the presence of pyridine. The mesylate is then displaced with various amines in the presence of K2CO3 and CH3CN at elevated temperature to produce compounds (6A). Amide derivatives (6B) are prepared as shown in steps 2b and 2c using previously described conditions.
Compounds of Formula V may also be prepared by first introducing the amide functionality. Thus, compound (14) is first aminated as previously described [U.S. Pat. No. 5,723,462] and the amide derivatives converted to enaminone derivatives (6C) using conditions analogous to those for the preparation of (22) (Scheme 4). Compound (6C) is converted to various ethyl pyrazole derivatives as shown in steps 1b, 3a, and 3b using previously described methods. Those skilled in the art will recognize that compounds of Formula V containing a variety of RA groups, such as alkyl, alkoxy ethyl, and variously substituted aminoethyl groups, may be prepared using methods analogous to those depicted in Scheme 6.
Those skilled in the art will also recognize that compounds of Formula V, wherein R4xe2x95x90CH3, may be prepared from compound (25) (Scheme 5) using conditions analogous to those shown in Scheme 6. 
Scheme 7 illustrates the synthesis of isoxazole derivatives of Formula VI. In step 1, compound (22) from Scheme 4 is reacted with hydroxylamine hydrochloride in ethanol at 100xc2x0 C. to provide isoxazole (33). Analogous reaction of diketone (25) with hydroxylamine hydrochloride affords the methyl isoxazole (35). Amination of (33) and (35) is accomplished in steps 2 and 2a using previously described 
The synthesis of compounds of Formula VII and Formula VIII is outlined in Scheme 8. In Scheme 8 step 1, ketone (15) from Scheme 2 is brominated with a suitable brominating agent such as 1,3-dibromo-4,4-dimethylhydantoin. The resulting bromoketone (37) is reacted with various amidines in step 2 to give the corresponding imidazoles (38). Typically, the amidine hydrochloride is used in the presence of excess base in 1,4-dioxane as solvent. Alternatively, bromoketone (37) can be reacted with thioamides to form thiazole derivatives (40). The esters (38) and (40) react to form amides as in steps 3 and 3a as previously described. Examples in the present invention of Formula VII and VIII with k=1 are formed using entirely analogous procedures. 
Scheme 9 illustrates the synthesis of fused imidazo derivatives (46). Step 1 involves a regioselective Schmidt type rearrangement of the ketone (42). The resulting amide (43) is converted to the thioamide (44) in Step 2. Thioamide (44) is efficiently converted to amidine (44) in the presence of mercury (II) acetate. Treatment of (44) with concentrated hydrochloric acid in Step 4 followed by amination of the ester in Step 5 provides the desired amide (46). 
Scheme 10 illustrates the synthesis of 7H-pyrrolo [2,3c][1,5] naphthyridine derivatives (55). Step 1 involves reaction of nitropyridine derivative (47) with 1-chloromethane-sulfonyl-4-methyl-benzene in the presence of strong base. In Step 2, (48) is alkylated with ethyl bromoacetate in the presence of base. Catalytic hydrogenation of (49) in Step 3 efficiently provides 3-aminopyridine derivative (50) which is subsequently protected in Step 4 using carbobenzyloxy chloride to provide (51). Heating (51) with strong base in Step 5 yields the acrylic acid derivative (52). Intermediate (52) is converted the pyrrole (53) in Step 6 using tosylmethyl isocyamide and base. Reaction of (53) with phosphorous oxychloride in the presence of DMF provides cyclized produce (54). In Step 8, ester derivative (54) is conveniently converted to amide (55) by reaction with aryl and heteroaryl amines in the presence of trimethyl aluminum. Preparation of 7H-pyrrolo [2,3c] [1,5] naphthyridine derivatives according to Scheme 10 is further illustrated by Example 21b.
Scheme 11 illustrates the synthesis of 3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene derivatives (62). In Step 1, acrylic acid derivative (56) is converted the pyrrole (57) in using tosylmethyl isocyamide and base. Step 2 involves reaction of pyrrole (57) with phosphorous oxychloride in the presence of DMF to obtain the aldehyde (58). Catalytic hydrogenation of nitrile (58) results in cyclized product (59) which is converted in Step 4 to amide (60) using trimethyl aluminum in the presence of an appropriate aryl or heteroaryl amine. In optional Steps 4xe2x80x2 and 5xe2x80x2, (59) is converted to N-alkylated product (61) via reductive amination and subsequently reacted to form amide (62). Preparation of 3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene derivatives according to Scheme 11 is further illustrated by Examples 21d and 21e.
Scheme 12 illustrates the synthesis of 5-methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene derivatives (74). In Step 1, 2-methylpyridine (63) is oxidized to aldehyde (64) in the presence of selenium dioxide. The aldehyde group in (64) is protected as the dimethyl ketal (65) in Step 2. Reduction of (64) in Step 3 using lithium aluminum hydride followed by oxidation to aldehyde in Step 4 using manganese dioxide provides aldehyde (67). Reductive amination of (67) in Step 5 with N-benzyl methyl amine provides (68) which is deprotected under acidic conditions in Step 6 to aldehyde (69). In Step 7, aldehyde (69) is reacted with triethylphosphoro-acetate and potassium bis(trimethylsilyl) amide to form acrylic acid derivative (70). In Step 8, reaction of (70) with tosylmethyl isocyamide and base provides pyrrole (71). Reaction of (71) with phosphorous oxychloride and DMF in Step 9 provides aldehyde (72) which is subsequently hydrogenated in Step 10 to provide cyclized product (73). Ester (73) is conveniently converted to amide (74) in the presence of trimethyl aluminum and an appropriate aryl or heteroaryl amine. Preparation of 5-methyl-3,4,5,6-tetrahydro-3,5,10-triaza-benzo(e)azulene derivatives according to Scheme 12 is further illustrated by Example 21f.
Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general the need for such protecting groups will be apparent to those skilled in the art of organic synthesis as well as the conditions necessary to attach and remove such groups.
The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them.